Epidemiological studies indicate waterpipe use has risen to the level of a ?global epidemic?. New and long-time smokers have misconceptions regarding the filtration ability of the pipe?s bowl liquid and toxicity of components drawn into the lungs. Cigarette tobacco smoke (CTS) research has identified a large library of harmful components that may be found in the tobacco pyrolysis products of waterpipe tobacco smoke (WTS). WTS is made more complex because it includes charcoal heat source combustion products and pyrolysis products, not found in CTS, from the shisha?s humectants and flavorants. Compared with CTS research, analysis of WTS and its toxicity is in the early stages. The most effective plan is to apply best practices from successful related fields. Air quality research findings are a currently overlooked connection. Air quality research has conclusively demonstrated that PM2.5 and Ultrafine (UF) particulate are a health hazard with EPA and WHO regulations in place to protect the public health. Therefore, instead of assuming that chemical toxicants are the only route to WTS harm, the proposed research includes physical and toxicological characterization to identify waterpipe configurations and smoking regimes that generate WTS profiles causing negative impacts due the number and size of the particles present, as well as those warranting targeted analysis due to damage caused by chemical composition. Environmental Tobacco Smoke (ETS) in a waterpipe caf and mainstream smoke certainly contain high concentrations of PM2.5 and UFP but seep through the cracks of current regulatory policy due to lack of direct study. The proposed project will characterize WTS as a collection of particulates that may harm health due to its physical characteristics to provide evidence by which policy might connect air quality and WTS regulations. Because particulate formation is affected by waterpipe configuration, the physical properties of particles generated when pipe height, charcoal vs. non-charcoal heat source, shisha and hose length and material are varied will be determined, informing regulation of waterpipe configuration based on air quality metrics. These data will indicate which configurations warrant systematic characterization as a function of variations in smoking regimes. Parallel investigations will determine the relative cytotoxicity of WTS generated by the different waterpipe configurations and smoking regimes. These investigations will advance the field by using whole smoke, not resuspended condensate or vapor separately, and lung cells grown as polar sheets and exposed to smoke at the air-liquid interface, thereby increasing physiological relevance. The cytotoxicity data will identify configurations requiring regulation based on harm caused by WTS physical or chemical characteristics. While both lines of investigation provide data important to understanding the health impacts of WTS and regulatable aspects of pipe configuration that can reduce harm, they also allow recognition of pipe configurations where WTS profiles are acting as physical toxicants, and chemical composition characterization is thus efficiently targeted only for those profiles where chemical toxicity is indicated.